In the field of obstetrics, one of the most important problems is the management of preterm labor. A significant number of the pregnancies progressing past 20 weeks of gestation experience premature labor and delivery, which is a leading cause of neonatal morbidity and mortality. Despite major advances in neonatal care, retention of the fetus in utero is preferred in most instances.
Tocolytic (uterine-relaxing) agents that are currently in use include .beta..sub.2 -adrenergic agonists, magnesium sulfate and ethanol. Ritodrine, the leading .beta..sub.2 -adrenergic agonist, causes a number of cardiovascular and metabolic side effects in the mother, including tachycardia, increased renin secretion, hyperglycemia (and reactive hypoglycemia in the infant). Other .beta..sub.2 -adrenergic agonists, including terbutaline and albuterol have side effects similar to those of ritodrine. Magnesium sulfate at plasma concentrations above the therapeutic range of 4 to 8 mg/dL can cause inhibition of cardiac conduction and neuromuscular transmission, respiratory depression and cardiac arrest, thus making this agent unsuitable when renal function is impaired. Ethanol is as effective as ritodrine in preventing premature labor, but it does not produce a corresponding reduction in the incidence of fetal respiratory distress that administration of ritodrine does.
It has been proposed that a selective oxytocin antagonist would be the ideal tocolytic agent. In the last few years, evidence has accumulated to strongly suggest that the hormone oxytocin is the physiological initiator of labor in several mammalian species including humans. Oxytocin is believed to exert this effect in part by directly contracting the uterine myometrium and in part by enhancing the synthesis and release of contractile prostaglandins from the uterine endometrium/decidua. These prostaglandins may, in addition, be important in the cervical ripening process. By these mechanisms, the process of labor (term and preterm) is initiated by a heightened sensitivity of the uterus to oxytocin, resulting in part as a result of a well-documented increase in the number of oxytocin receptors in this tissue. This "up-regulation" of oxytocin receptors and enhanced uterine sensitivity appears to be due to trophic effects of rising plasma levels of estrogen towards term. By blocking oxytocin, one would block both the direct (contractile) and indirect (enhanced prostaglandin synthesis) effects of oxytocin on the uterus. A selective oxytocin blocker, or antagonist, would likely be more efficacious for treating preterm labor than current regimens. In addition, since oxytocin at term has major effects only on the uterus, such a oxytocin antagonizing compound would be expected to have few, if any, side effects.
The compounds of the present invention can also be useful in the treatment of dysmenorrhea. This condition is characterized by cyclic pain associated with menses during ovulatory cycles. The pain is thought to result from uterine contractions and ischemia, probably mediated by the effect of prostaglandins produced in the secretory endometrium. By blocking both the direct and indirect effects of oxytocin on the uterus, a selective oxytocin antagonist can be more efficacious for treating dysmenorrhea then current regimens.
It is, therefore, a purpose of this invention to provide substances which more effectively antagonize the function of oxytocin in disease states in animals, preferably mammals, especially in humans. It is another purpose of this invention to prepare novel compounds which more selectively inhibit oxytocin. It is still another purpose of this invention to provide a method of antagonizing the functions of oxytocin in disease states in mammals. It is also a purpose of this invention to develop a method of preventing or treating oxytocin-related disorders of preterm labor and dysmenorrhea by antagonizing oxytocin.
It has now been found that compounds of formula I are antagonists of oxytocin and bind to the oxytocin receptor. When the oxytocin receptor is bound by the compounds of the present invention, oxytocin is antagonized by being blocked from its receptor and thus being unable to exert its biologic or pharmacologic effects. These compounds are useful in the treatment and prevention of oxytocin-related disorders of animals, preferably mammals and especially humans. These disorders are primarily preterm labor and dysmenorrhea. The compounds would also find usefulness for stoppage of labor preparation to Cesarean delivery.
The compounds of the present invention are those of the general structural formula: ##STR2## and the pharmaceutically acceptable salts thereof, wherein R is H or alkylsulfonylalkyl,
R.sup.1 is hydrogen or hydroxy, PA1 R.sup.2 is one of N-(R.sup.3).sub.2, Het-R.sup.4 or Alk-R.sup.5, wherein PA1 R.sup.3 is independently one or more of hydrogen, cycloalkyl, pyrrolidinyl substituted by oxo, carboxyalkyl or alkoxycarbonyalkyl, alkyl substituted by alkylamino, alkylcarbamate, alkylcarbonyl, alkylsulfonyl, alkylthio, alkoxycarbonyl, amino, aminocarbonyl, carboxyl, dialkylamino, dialkylaminoaryl, hydroxyl, sulfhydryl, or substituted or unsubstituted 5 or 6 membered heterocyclic rings having 1 or 2 heteroatoms where said heteroatom is N and said ring substitutent is aralkoxycarbonyl; PA1 Het is a 5 or 6 membered heterocyclic ring having 1 heteroatom wherein said heteroatom is N, PA1 R.sup.4 is alkylsulfonyl, alkylsulfonylamino, alkylsulfonyloxy, alkylaminocarbonyl, alkylcarbamatealkylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, aminocarbonylalkyl, aminoalkylcarbonyl, aralkoxycarbonyl, carbonyl, dialkylaminocarbonyl, dialkylaminoalkylcarbonyl, diaminoalkylcarbonyl, halogenalkyl, halogenalkylcarbonyl, halogenalkoxycarbonyl, hydroxy, hydroxyalkyl, hydroxyalkylcarbonyl, imidazolylalkylcarbonyl imidizinylalkylcarbonyl, or phthalimidinylalkyl; with the proviso for Het-R4 that Het cannot be mono-substituted by any one of the alkoxycarbonyl, alkoxycarbonylalkyl, aralkoxycarbonyl or hydroxy; PA1 Alk is alkyl, PA1 R.sup.5 is independently one or more of R.sup.6, or Het-R.sup.7 wherein R.sup.6 is independently one or more of alkylcarbamate, alkylcarbonylamino substituted by substituted imidazolyl or pyrrolidinyl rings where said ring substituent is alkyl or alkoxycarbonylalky, alkylcarbamatecycloalkyl, alkylcarbonylaminoalkylsulfonyl, alkylimidazolylthio, alkylimidizinylthio, alkylimidazolylalkylthio, alkylimidizinylalkylthio, alkylpyrrolidinylthio, alkylpyrrolidinylalkylthio, alkylsulfonyl, alkylsulfonylamino, alkylsulfonylalkylamino, alkoxycarbonyl, alkoxycarbonylalkylamine, alkoxycarbonylalkylcarbonylamine, alkoxycarbonylalkylsulfonylamine, amino, aminocarbonyl, aminoalkylcarbonylamino, aminocarbonylalkylsulfonyl, aminocarbonylalkylearbonylamino, aralkoxy, aralkoxycarbonyl, aralkylcarbamate, arylcarbamate, arylcarbamatecarbonylamino, arylcarbamatealkylcarbonylamino, carboxyalkylamino, carboxyalkylcarbonylamino, carboxyalkylsulfonylamino, cyano, cyanoalkylcarbonylamino, dialkylaminoalkylcarbonylamino or oxo, with the proviso for R.sup.6 that R.sup.6 cannot be mono-substituted by any one of alkoxycarbonyl, alkylcarbamate, alkylsulfonyl, aralkylcarbamate, aralkoxy, amino, aminocarbonyl, or oxo; PA1 Het is as defined before; PA1 R.sup.7 is one or more of alkyl, imidazolinylalkylcarbonyl, imidazolinylalkylcarbonylamino, oxo, pyrrolidinylalkylcarbonyl, pyrrolidinylalkylcarbonylamino or alkylamino substituted by one or more of alkylcarbamate, alkylcarbamatealkylcarbonyl, alkylsulfonylalkyl, amino, aralkoxyalkyl or oxo with the proviso for Het-R.sup.7 that Het cannot be mono-substituted by alkyl alkylamino, dialkylamino or oxo.
Salts encompassed within the term "pharmaceutically acceptable salts" refer to non-toxic salts of the compounds of this invention which are generally prepared by reacting the free base with a suitable organic or inorganic acid. Representative salts include the following salts:
______________________________________ Acetate Lactobionate Benzenesulfonate Laurate Benzoate Malate Bicarbonate Maleate Bisulfate Mandelate Bitartrate Mesylate Borate Methylbromide Bromide Methylnitrate Calcium Edetate Methylsulfate Camsylate Mucate Carbonate Napsylate Chloride Nitrate Clavulanate N-methylglucamine Citrate Oxalate Dihydrochloride Pamoate (Embonate) Edetate Palmitate Edisylate Pantothenate Estolate Phosphate/diphosphate Esylate Polygalacturonate Fumarate Salicylate Gluceptate Stearate Gluconate Subacetate Glutamate Succinate Glycollylarsanilate Tannate Hexylresorcinate Tartrate Hydrabamine Teoclate Hydrobromide Tosylate Hydrocloride Triethiodide Hydroxynaphthoate Valerate Iodide Isethionate Lactate ______________________________________
The term "pharmacologically effective amount" shall mean that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by a researcher or clinician.
The term "alkyl" shall mean straight or branched chain alkanes, alkenes and alkynes with one or more degrees of unsaturation at any position on the chain, of one to ten total carbon atoms or any number within this range.
The term "aryl" shall mean phenyl.
The term "cycloalkyl" shall mean cyclic rings of alkanes, alkenes or alkynes with one or more degrees of unsaturation at any position of the ring, of three to eight total carbon atoms.
Whenever the terms "alkyl" or "aryl" or either of their prefix roots appear in a name of a substituent (e.g. aralkoxyaryloxy) they shall be interpreted as including those limitations given above for "alkyl" and "aryl". Designated numbers of carbon atoms (e.g. C.sub.1-10) shall refer independently to the numberof carbon atoms in an alkyl or cyclic alkyl moiety or to the alkyl portion of a larger substituent in which alkyl appears as its prefix root.
The term "oxo" shall refer to the substituent=O.
The term "halogen" shall include iodine, bromine, chlorine and fluorine.
The term "preterm labor" shall mean expulsion from the uterus of a viable infant before the normal end of gestation, or more particularly, onset of labor with effacement and dilation of the cervix before the 37th week of gestation. It may or may not be associated with vaginal bleeding or rupture of the membranes.
The term "dysmenorrhea" shall mean painful menstruation.
The term "cesarean delivery" shall mean incision through the abdominal and uterine walls for delivery of a fetus.
The term "substituted" shall be deemed to include multiple degrees of substitution by a named substitutent.
The ability of the compounds of formula I to antagonize oxytocin makes these compounds useful as pharmacologic agents for mammals, especially for humans, for the treatment and prevention of disorders wherein oxytocin may be involved. Examples of such disorders include preterm labor and especially dysmenorrhea. These compounds may also find usefulness for stoppage of labor preparatory to Cesarean delivery.
Because of the known relationship of vasopressin to oxytocin, the compounds of the present invention are also useful as vasopressin antagonists. Vasopressin antagonists are useful in the treatment or prevention of disease states involving vasopressin disorders, including their use as diuretics and their use in congestive heart failure.
The compounds of the present invention can be administered in such oral dosage forms as tablets, capsules (each including timed release and sustained release formulations), pills, powders, granules, elixers, tinctures, suspensions, syrups and emulsions. Likewise, they may also be administered in intravenous (both bolus and infusion), intraperitoneal, subcutaneous or intramuscular form, all using forms well known to those of ordinary skill in the pharmaceutical arts. An effective but non-toxic amount of the compound desired can be employed as a tocolytic agent.
The dosage regimen utilizing the compounds of the present invention is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed. An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.
Oral dosages of the present invention, when used for the indicated effects, will range between about 0.3-6.0 gm/day orally. Intravenously, the most preferred doses will range from 0.1 to about 10 mg/minute during a constant rate infusion. Advantageously, compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily. Furthermore, preferred compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittant throughout the dosage regimen.
In the methods of the present invention, the compounds herein described in detail can form the active ingredient, and are typically administered in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as "carrier" materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.
For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, zanthan gum and the like.
The compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
Compounds of the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled. The compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues. Furthermore, the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polyactic acid, polepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
The compounds of formula I can be prepared readily according to the following reaction Schemes (in which all variables are as defined before) and Examples or modifications thereof using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants which are themselves known to those of ordinary skill in this art, but are not mentioned in greater detail.
The most preferred compounds of the invention are any or all of those specifically set forth in these examples. These compounds are not, however, to be construed as forming the only genus that is considered as the invention, and any combination of the compounds or their moieties may itself form a genus. The following examples further illustrate details for the preparation of the compounds of the present invention. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds. All temperatures are degrees Celsius unless noted otherwise. ##STR3##